In vivo activation of midbrain dopamine neurons via sensitized, high-affinity alpha 6 nicotinic acetylcholine receptors.
Alpha6-containing (alpha6*) nicotinic ACh receptors (nAChRs) are selectively expressed in dopamine (DA) neurons and participate in cholinergic transmission. We generated and studied mice with gain-of-function alpha6* nAChRs, which isolate and amplify cholinergic control of DA transmission. In contrast to gene knockouts or pharmacological blockers, which show necessity, we show that activating alpha6* nAChRs and DA neurons is sufficient to cause locomotor hyperactivity. alpha6(L9'S) mice are hyperactive in their home cage and fail to habituate to a novel environment. Selective activation of alpha6* nAChRs with low doses of nicotine, by stimulating DA but not GABA neurons, exaggerates these phenotypes and produces a hyperdopaminergic state in vivo. Experiments with additional nicotinic drugs show that altering agonist efficacy at alpha6* provides fine tuning of DA release and locomotor responses. alpha6*-specific agonists or antagonists may, by targeting endogenous cholinergic mechanisms in midbrain or striatum, provide a method for manipulating DA transmission in neural disorders.
Drenan
Ryan M
RM
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Grady
Sharon R
SR
Whiteaker
Paul
P
McClure-Begley
Tristan
T
McKinney
Sheri
S
Miwa
Julie M
JM
Bupp
Sujata
S
Heintz
Nathaniel
N
McIntosh
J Michael
JM
Bencherif
Merouane
M
Marks
Michael J
MJ
Lester
Henry A
HA
D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004298:Dopamine / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008636:Mesencephalon / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011995:Recombination, Genetic; D009435:Synaptic Transmission / Q000235:genetics
D011978:Receptors, Nicotinic; C104518:nicotinic receptor alpha6; D004298:Dopamine